Adipose-derived stem cells promote glycolysis and peritoneal metastasis via TGF-ß1/SMAD3/ANGPTL4 axis in colorectal cancer.

Peritoneal metastasis, the third most common metastasis in colorectal cancer (CRC), has a poor prognosis for the rapid progression and limited therapeutic strategy. However, the molecular characteristics and pathogenesis of CRC peritoneal metastasis are poorly understood. Here, we aimed to elucidate the action and mechanism of adipose-derived stem cells (ADSCs), a prominent component of the peritoneal microenvironment, in CRC peritoneal metastasis formation. Database analysis indicated that ADSCs infiltration was increased in CRC peritoneal metastases, and high expression levels of ADSCs marker genes predicted a poor prognosis. Then we investigated the effect of ADSCs on CRC cells in vitro and in vivo. The results revealed that CRC cells co-cultured with ADSCs exhibited stronger metastatic property and anoikis resistance, and ADSCs boosted the intraperitoneal seeding of CRC cells. Furthermore, RNA sequencing was carried out to identify the key target gene, angiopoietin like 4 (ANGPTL4), which was upregulated in CRC specimens, especially in peritoneal metastases. Mechanistically, TGF-ß1 secreted by ADSCs activated SMAD3 in CRC cells, and chromatin immunoprecipitation assay showed that SMAD3 facilitated ANGPTL4 transcription by directly binding to ANGPTL4 promoter. The ANGPTL4 upregulation was essential for ADSCs to promote glycolysis and anoikis resistance in CRC. Importantly, simultaneously targeting TGF-ß signaling and ANGPTL4 efficiently reduced intraperitoneal seeding in vivo. In conclusion, this study indicates that tumor-infiltrating ADSCs promote glycolysis and anoikis resistance in CRC cells and ultimately facilitate peritoneal metastasis via the TGF-ß1/SMAD3/ANGPTL4 axis. The dual-targeting of TGF-ß signaling and ANGPTL4 may be a feasible therapeutic strategy for CRC peritoneal metastasis.

Inhibition of PFKFB3 in HER2-positive gastric cancer improves sensitivity to trastuzumab by inducing tumour vessel normalisation.

BACKGROUND: Multiple mechanisms have been proposed that lead to reduced effectiveness of trastuzumab in HER2-positive gastric cancer (GC), yet resistance to trastuzumab remains a challenge in clinics. METHODS: We established trastuzumab-resistant cells and patient-derived xenografts models to measure metabolic levels and vascular density and shape. The HER2-positive GC patient samples were used to determine clinical significance. We also measured protein expression and phosphorylation modifications to determine those alterations related to resistance. In vivo studies combining inhibitor of PFKFB3 with trastuzumab corroborated the in vitro findings. RESULTS: The 6-phosphofructo-2-kinase (PFKFB3)-mediated trastuzumab resistance pathways in HER2-positive GC by activating the glycolytic pathway. We also found vessels are chaotic and destabilised in the tumour during the trastuzumab resistance process. Inhibition of PFKFB3 significantly diminished tumour proliferation and promoted vessel normalisation in the patient-derived xenograft model. Mechanistically, PFKFB3 promoted the secretion of CXCL8 into the tumour microenvironment, and phosphorylated Ser1151 of ERBB2, enhancing the transcription of CXCL8 by activating the PI3K/AKT/NFκB p65 pathway. CONCLUSIONS: Our current findings discover that PFKFB3 inhibitors might be effective tools to overcome adjuvant therapy resistance in HER2-positive GC and reshaping the microenvironment by normalising tumour vessels is a novel strategy to overcome trastuzumab resistance.

Surgical Treatment of Retrograde Type A Aortic Dissection After Thoracic Endovascular Aortic Repair.

Data are scarce regarding retrograde type A dissection (RTAD) after thoracic endovascular aortic repair (TEVAR). This study aimed to investigate the clinical characteristics and surgical treatment outcomes of patients who developed RTAD after TEVAR.From January 2015 to January 2020, 25 consecutive patients (aged 52 ± 11.69 years) of RTAD after TEVAR received open surgery. All patients received total arch replacement (TAR) with the frozen elephant trunk (FET). The proximal part of the TEVAR stent was removed using a wire scissor. The distal part of the TEVAR stent in the descending aorta was preserved. Data of 50 random patients of type A aortic dissection without prior TEVAR were collected during the same period. We compared the perioperative and midterm follow-up outcomes between patients with prior TEVAR and patients without prior TEVAR.The mean cardiopulmonary bypass time, aortic cross-clamp time, and deep hypothermic circulatory arrest time were 173.7 ± 44.1, 109.5 ± 31.4, and 21.6 ± 6.8 minutes in the RTAD group, respectively. These times are similar to those of the no-RTAD group. The median interval between the initial TEVAR procedure and RTAD was 8.5 months (range, 0-72 months). New entry tears that were induced by the proximal end of the TEVAR stent were found in 23 (92%) patients of the RTAD group. There were no significant differences in major adverse events and overall survival between the two groups.TAR with the FET technique was feasible for the treatment of RTAD after TEVAR, with acceptable early and midterm results.

Yes associated protein 1 promotes resistance to 5-fluorouracil in gastric cancer by regulating GLUT3-dependent glycometabolism reprogramming of tumor-associated macrophages.

The antimetabolite 5-fluorouracil (5-FU) is a widely used chemotherapy regimen for the treatment of gastric cancer (GC). However, resistance to 5-FU remains a major drawback in the clinical use. The treatments of anti-tumor chemo-agents recruit tumor associated macrophages (TAMs) which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we demonstrate that YAP1 is overexpressed in resistant GC tissues compared to sensitive GC tissues. Further, IL-3 secreted by YAP1-overexpressed GC could skew macrophage polarization to M2-like phenotype and inducing GLUT3-depended glycolysis program. Meanwhile, polarized M2 macrophages enhance 5-FU resistance in tumor cells by secreting CCL8 and activating phosphorylation of JAK1/STAT3 signaling pathway.

SLC2A3 promotes macrophage infiltration by glycolysis reprogramming in gastric cancer.

BACKGROUND: Tumors display a high rate of glucose metabolism and the SLC2A (also known as GLUT) gene family may be central regulators of cellular glucose uptake. However, roles of SLC2A family in mechanism of metabolite communication with immunity in gastric cancer remains unknown. METHODS: Bioinformatics analysis and IHC staining were used to reveal the expression of SLC2A3 in gastric cancer and the correlation with survival prognosis. Real-time PCR, western blots, OCR, ECAR, lactate production and glucose uptake assays were applied to determine the effect of SLC2A3 on glycolysis reprogramming. We then investigated the consequences of SLC2A3 upregulation or inhibition on aerobic glycolysis, also explored the underlying mechanism. Bioinformatics analysis and in vitro and in vivo research were used to reveal the role of SLC2A3 in macrophage infiltration and transition. RESULTS: Here, we show that SLC2A3 acts as a tumor promoter and accelerates aerobic glycolysis in GC cells. Mechanistically, the SLC2A3-STAT3-SLC2A3 feedback loop could promote phosphorylation of the STAT3 signaling pathway and downstream glycolytic targeting genes. Moreover, SLC2A3 potentially contributes to M2 subtype transition of macrophage infiltration in the GC microenvironment. CONCLUSIONS: SLC2A3 could be used as a prognostic biomarker to determine prognosis and immune infiltration in GC and may provide an intervention strategy for GC therapy.

Abiraterone acetate and docetaxel with androgen deprivation therapy in high-volume metastatic hormone-sensitive prostate cancer in China: an indirect treatment comparison and cost analysis.

BACKGROUND: To conduct an indirect treatment comparison of patients with high-volume mHSPC and a cost analysis between Abi-ADT and Doc-ADT therapies in China. METHODS: The Bucher technique for indirect treatment comparison was used. A cost analysis was conducted from both healthcare and patient perspectives. RESULTS: The indirect treatment comparison demonstrated no significant difference in PFS for Abi-ADT versus Doc-ADT (HR: 0.84, 95% CI 0.66-1.07). Doc-ADT therapy costs less than Abi-ADT, with potential savings of up to RMB 887,057 per patient from the healthcare perspective and RMB 226,210 per patient from the patient perspective. CONCLUSIONS: No significant differences in PFS between Doc-ADT and Abi-ADT therapy for patients with high-volume mHSPC. Doc-ADT therapy is a cost-saving alternative to Abi-ADT in China.

Aortic Valve Replacement with Bovine Pericardium in Patients with Aortic Valve Regurgitation.

This study aimed to analyze the early and mid-term outcomes of aortic valve replacement with bovine pericardium in the treatment of aortic valve regurgitation.From January 2015 to March 2018, 36 patients (19 men; mean ± standard deviation [SD] age, 46.70 ± 16.60 years) underwent aortic valve replacement with bovine pericardium. The bovine pericardium was intraoperatively measured and shaped using an Ozaki template, according to the shape and size of the individual patient's aortic valve leaflets. Additional procedures were performed, including ventricular septal defect repair in 5 cases, mitral valve reconstruction in 6 cases, tricuspid valve reconstruction in 6 cases, and coronary artery bypass grafting in 3 cases.There were no perioperative deaths. One elderly patient with postoperative respiratory failure recovered after symptomatic treatment. One patient with frequent ventricular tachycardia after intraoperative cardiac re-jump underwent intra-aortic balloon counterpulsation (IABP), and the IABP device was successfully removed on the second postoperative day. Within the first 6 months of follow-up, there were no death events, no reoperation events, and no additional thromboembolic events. Follow-up echocardiography was performed for 6 months, with average left ventricular ejection fraction of 62.01 ± 3.21%, mean transvalvular pressure gradient of 11.17 ± 4.90 mmHg, and mean aortic valve velocity of 1.60 ± 0.58 m/s. Compared with the preoperative transthoracic echocardiography findings, the results at the six-month follow-up were statistically significant (P < 0.05). Mild aortic valve regurgitation occurred in 2 patients (5.56%), whereas other patients had no or only minimal aortic valve regurgitation (n = 34, 94.44%). Moderate aortic valve regurgitation occurred in one patient at 9 months after the initial operation. This was found to be due to infective endocarditis, and a biological valve was finally implanted.Aortic valve replacement with bovine pericardium in the treatment of aortic valve regurgitation is feasible, and good early and mid-term results are achieved. Long-term results need to be followed up in the future.

MicroRNA-125b-5p attenuates lipopolysaccharide-induced monocyte chemoattractant protein-1 production by targeting inhibiting LACTB in THP-1 macrophages.

BACKGROUND: Increasing evidence has shown that gene beta-lactamases (LACTB) has effect on obesity. Recent studies demonstrate that miR-125b-5p is a potential small molecular target to prevent atherosclerosis obliterans which may be inflammation-associated. However, the mechanism underlying miR-125b-5p on arteriosclerosis development, the association between miR-125b-5p and LACTB is still unknown. METHODS AND RESULTS: In this study, we found that miR-125b-5p was down-regulated while LACTB was up-regulated in atherosclerotic plaques. Our results showed that LACTB was a potential target of miR-125b-5p based on bioinformatics analyses and dual-luciferase reporter assays. Moreover, miR-125b-5p directly inhibited LACTB protein and mRNA expression by targeting LACTB 3'UTR. Meanwhile, the expression of monocyte chemotactic protein-1 (MCP-1) was decreased by miR-125b-5p mimics treatment in THP-1 macrophages. We also demonstrated that the level of MCP-1 was markedly increased when transfected with LACTB. In addition, the upregulation of MCP-1 expression through miR-125b-5p inhibitors was attenuate by siRNA-LACTB treatment in LPS-stimulated THP-1 macrophages. CONCLUSIONS: MiR-125b-5p attenuates the secretion of MCP-1 by directly targeting inhibiting LACTB in LPS-stimulated THP-1 macrophages.

Combined use of transmyocardial laser revascularization and endothelial progenitor cells enhances neovascularization and regional contractility in a canine model of ischemic hearts.

The purpose of this study was to determine the combined effect of transmyocardial laser revascularization (TMLR) and the implantation of endothelial progenitor cells (EPCs) on cardiac function of ischemic hearts in canines. The left anterior descending artery (LAD) was occluded to establish the canine model of acute myocardial infarct (AMI). Four weeks later, the animals were randomly divided into four groups: TMLR group, in which transmyocardial laser-induced channels were established at the ischemic region; EPCs+TMLR group, in which EPCs were locally transplanted into laser-induced channels at the ischemic region; EPCs group, in which the EPCs were injected into the ischemic region; control group, in which the AMI animals received neither TMLR nor EPCs. The peripheral blood (50 mL) was sampled in all groups. Mononuclear cells from the peripheral blood were separated and cultured to obtain spindle-shaped attaching (AT) cells in vitro. AT cells were labeled with 1, 1'-dioctadecyl-1 to 3,3, 3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) before injecting into the laser-induced channels or ischemic region. Four weeks after the first operation, TMLR was performed in the TMLR group and EPCs+TMLR group, and at the same time, the EPCs originating from the AT cells were mixed with calcium alginate (CA). Then the EPCs-CA composites were implanted into myocardial channels induced by laser in the EPCs+TMLR group, and into the myocardial infarct area in the EPCs group. All dogs underwent echocardiography at second month after LAD occlusion. Finally the samples of myocardium around the LAD were subjected to histochemical and immunohistologic examinations. The results showed there was no significant difference in the diameter of left atrium and ventricle before treatment among all groups (P>0.05). Eight weeks after modeling, the regional contractility in the LAD territory in the EPCs+TMLR group was increased as compared with control group and TMLR group, but there was no significant difference between control group and TMLR group. Neoangiogenesis was observed in the EPCs+TMLR group, and the fibrosis was seen in the TMLR group. There was no significant difference in neoangiogenesis around the channels induced by laser among EPCs+TMLR, EPCs and TMLR groups. It was concluded that TMLR combined with EPCs could improve the regional and global cardiac function in AMI, and augment neovascularizaiton in channels of ischemic myocardium induced by laser.

[Retracted] FAM172A modulates apoptosis and proliferation of colon cancer cells via STAT1 binding to its promoter.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that lanes 1­3 of the EMSA results shown in Fig. 6 on p. 1278 were strikingly similar to data that had already appeared in a different form in the following publication by different authors at different research institutes: Qiu K, Li Z, Chen J, Wu S, Zhu X, Gao S, Gao J, Ren G and Zhou X: EIN3 and ORE1 accelerate degreening during ethylene­mediated leaf senescence by directly activating chlorophyll catabolic genes in Arabidopsis. PLoS Genet 11: e1005399, 2015. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 35: 1273­1280, 2016; DOI: 10.3892/or.2015.4485.

Prediction and prognosis of reintubation after surgery for Stanford type A aortic dissection.

Background: Reintubation is a serious adverse respiratory event after Stanford type A aortic dissection surgery (AADS), however, published studies focused on reintubation after AADS are very limited worldwide. The objectives of the current study were to establish an early risk prediction model for reintubation after AADS and to clarify its relationship with short-term and long-term prognosis. Methods: Patients undergoing AADS between 2016-2019 in a single institution were identified and divided into two groups based on whether reintubation was performed. Independent predictors were identified by univariable and multivariable analysis and a clinical prediction model was then established. Internal validation was performed using bootstrap method with 1,000 replications. The relationship between reintubation and clinical outcomes was determined by univariable and propensity score matching analysis. Results: Reintubation were performed in 72 of the 492 included patients (14.6%). Three preoperative and one intraoperative predictors for reintubation were identified by multivariable analysis, including older age, smoking history, renal insufficiency and transfusion of intraoperative red blood cells. The model established using the above four predictors showed moderate discrimination (AUC = 0.753, 95% CI, [0.695-0.811]), good calibration (Hosmer-Lemeshow χ2 value = 3.282, P = 0.915) and clinical utility. Risk stratification was performed and three risk intervals were identified. Reintubation was closely associated with poorer in-hospital outcomes, however, no statistically significant association between reintubation and long-term outcomes has been observed in patients who were discharged successfully after surgery. Conclusions: The requirement of reintubation after AADS is prevalent, closely related to adverse in-hospital outcomes, but there is no statistically significant association between reintubation and long-term outcomes. Predictors were identified and a risk model predicting reintubation was established, which may have clinical utility in early individualized risk assessment and targeted intervention.

Imperatorin alleviated endometriosis by inhibiting the activation of PI3K/Akt/NF-κB pathway in rats.

AIMS: Most therapeutic drugs of endometriosis have been contraceptives but symptoms recur in up to 75% of cases, which makes it a presses need to try to find novel and safer therapeutic drugs. Imperatorin is a furanocoumarin existing in many plants, possessing multiple activities, including anti-inflammatory. The purpose of this study was to assess the effects and mechanisms of imperatorin in endometriosis. MAIN METHODS: Ectopic endometrial volume and hematoxylin-eosin staining were used to estimate the effects of imperatorin in experimental endometriosis model rats. Potential mechanisms of imperatorin in endometriosis were systematically analyzed by network pharmacology and molecular docking. Western blotting and enzyme-linked immunosorbent assay were employed to evaluate proteins expression and cytokines levels in PI3K/Akt/NF-κB pathway. KEY FINDINGS: Imperatorin could significantly inhibit the growth and ameliorate the histopathological features of ectopic endometrium in experimental endometriosis rats. Network pharmacology approaches showed that imperatorin might regulate inflammatory response and cellular function via primarily affecting PI3K-Akt pathway, Endocrine resistance, Th17 cell differentiation in endometriosis. Moreover, 7 core targets (PIK3CA, AKT1, SRC, MAPK8, MAPK14, ERBB2 and CCND1) resulted from the intersection of KEGG and PPI network topological analysis were used to dock with imperatorin, which indicated that imperatorin could preferably fit in the binding pocket of the above target proteins, except for CCND1. Lastly, imperatorin markedly inhibited the activation of PI3K/Akt/NF-κB pathway via suppressing the phosphorylation levels of PI3K, Akt and p65 in the ectopic endometrium tissue. SIGNIFICANCE: Our findings revealed that imperatorin is a significant multi-target natural active ingredient for treatment endometriosis.

En Bloc Arch Reconstruction With the Frozen Elephant Trunk Technique for Acute Type a Aortic Dissection.

Objective: The study objective was to evaluate the effect of en bloc arch reconstruction with frozen elephant trunk (FET) technique for acute type A aortic dissection. Methods: 41 patients with acute Stanford type A dissection underwent en bloc arch reconstruction combined with FET implantation between April 2018 and August 2020. The mean age of the patients was 46 ± 13 years, and 9 patients were female. One patient had Marfan syndrome. Six patients had pericardial tamponade, 9 had pleural effusion, 5 had transient cerebral ischemic attack, and 3 had chronic kidney disease. Results: The hospital mortality rate was 9.8% (4 patients). 2 (4.9%) patients had stroke, 23 (56.1%) had acute kidney injury, and 5 (12.2%) had renal failure requiring hemodialysis. During follow-up, the rate of complete false lumen thrombosis was 91.6% (33/36) around the FET, 69.4% (25/36) at the diaphragmatic level, and 27.8% (10/36) at the superior mesenteric artery level. The true lumen diameter at the same three levels of the descending aorta increased significantly while the false lumen diameter reduced at the two levels: pulmonary bifurcation and the diaphragm. The 1-, 2-and 3-year actuarial survival rates were 90.2% [95% confidence interval (CI), 81.2-99.2], 84.2% (95% CI, 70.1-98.3) and 70.2% (95% CI, 42.2-98), respectively. Conclusions: In patients with acute type A dissection, en bloc arch reconstruction with FET technique appeared to be feasible and effective with early clinical follow-up results. Future studies including a large sample size and long-term follow-up are required to evaluate the efficacy.

A Caprini Risk Score-Based Cost-Effectiveness Analysis of Enoxaparin for the Thromboprophylaxis of Patients After Nonorthopedic Surgery in a Chinese Healthcare Setting.

BACKGROUND: Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is an important cause of post-surgery morbidity and mortality. However, it is unclear whether thromboprophylaxis with the low-molecular-weight heparin (LMWH) enoxaparin after non-orthopedic surgery could balance the cost and clinical outcomes or not. OBJECTIVES: The purpose of this research was to evaluate the cost-effectiveness of enoxaparin for the universal prophylaxis of VTE and associated long-term complications in patients after non-orthopedic surgery compared with no prevention in a Chinese healthcare setting. METHODS: A decision model, which included both acute VTE and long-term complications, was developed to assess the economic outcomes of the two strategies for patients after non-orthopedic surgery. Quality-adjusted life years (QALYs) and direct medical costs were measured over a 5-year horizon. Incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: Compared with no prevention, patients under enoxaparin treatment with Caprini risk scores of 3-4, 5-6, 7-8, and ≥ 9 increased by 0.012, 0.017, 0.034, and 0.102 in QALYs, respectively. The results were either that ICERs of thromboprophylaxis with enoxaparin over no prevention were lower than the thresholds or that thromboprophylaxis with enoxaparin was dominant. For patients with a Caprini risk score ≥ 9, thromboprophylaxis with enoxaparin is dominant across the whole drug use duration range. The sensitivity analysis confirmed the results. CONCLUSIONS: As the first analysis evaluating the economic outcomes of enoxaparin in patients undergoing general non-orthopedic surgery, this study suggests that thromboprophylaxis with enoxaparin is highly cost-effective compared with no prevention in patients with Caprini risk score ≥ 3.

Laparoscopic omental flap for the treatment of thoracic aortic graft infection: report of two cases and review of the literature.

BACKGROUND: Thoracic aortic graft infection (TAGI) is a rare and serious complication after surgery for which the treatment is controversial and challenging. Rather than following the traditional surgical strategy of graft replacement and extensive debridement, we have chosen to preserve the graft and cover it by a laparoscopic omental flap. In this article, we describe the clinical manifestation, diagnostic modalities, and treatment of this disease and analyze the role of laparoscopic omental flaps in its treatment. CASE PRESENTATION: We present two cases of thoracic aortic graft infections that had undergone surgical graft replacement for acute Stanford type A dissection. Their clinical manifestation of infection was atypical, with computed tomography suggesting infection of the grafts. Both patients were successfully treated with debridement, laparoscopic omental transposition, and antibiotics. The first case, a 55-year-old male, was found to have an infection at the aortic arch. The second case is a 52-year-old male who was found to have infection at the ascending aorta and arch. Surprisingly, both intraoperative cultures were negative. The infections were brought under control and the patients recovered steadily after surgery. Early follow-up results showed no signs of graft infection. CONCLUSION: These findings suggest that graft replacement for the treatment of TAGI is not always necessary in selected patients. Conservative surgical treatment, including laparoscopic omental transposition, is effective and less invasive for treating TAGI.

CD73 promotes tumor metastasis by modulating RICS/RhoA signaling and EMT in gastric cancer.

Tumor microenvironment plays vital roles in shaping cancer diversity, and CD73 (ecto-5'-nucleotidase; NT5E) is an emerging immune checkpoint in modulating cancer progression via conversion of immunostimulatory ATP into immunosuppressive adenosine. However, how the CD73 is regulated and how it functions in the progression of cancer are largely unknown. Here, we showed that CD73 was overexpressed and correlated with poor prognosis of gastric cancer. CD73 links adenosinergic signaling in microenvironment switching to induction of epithelial-to-mesenchymal transition phenotype in gastric cancer during metastasis. Further pathway and gene set enrichment analysis of transcriptome data revealed the modulation role of CD73 in RICS/RhoA signaling by its extracellular function in adenosinergic pathway, which subsequently inhibited phosphorylation of LIMK/cofilin and promoted ß-catenin activation. Pharmacological inhibition of CD73 adenosinergic signaling was found to induce RICS dysfunction. Dissemination and hematogenous metastasis model showed that targeting CD73 in gastric cancer could suppress experimental metastasis. To conclude, it substantiates CD73 as a target for treatment of gastric cancer metastasis and verifies RICS as an intracellular functional molecule linking CD73/adenosinergic signaling switching to RhoA/LIMK/cofilin pathway.

Comparative clinical effects and cost-effectiveness of maximum androgen blockade, docetaxel with androgen deprivation therapy and ADT alone for the treatment of mHSPC in China.

Aim: To compare the clinical effects and cost-effectiveness of maximum androgen blockade (MAB), docetaxel to androgen deprivation therapy (Doc-ADT) and ADT alone for the treatment of patients with metastatic hormone-sensitive prostate cancer in China. Methods: A network meta-analysis and a Markov model were adopted for effectiveness and economic evaluation. Results: The hazard ratios of overall survival and progression-free survival were 0.782 and 0.628 for Doc-ADT versus ADT alone; 0.897 and 0.824 for MAB versus ADT alone. Doc-ADT was cost-effective compared with MAB and ADT alone, with an incremental cost-effectiveness ratio of CNY 96,848 and CNY 67,758 per quality-adjusted life year, respectively. MAB was cost-effective compared with ADT alone, with an incremental cost-effectiveness ratio of CNY 137,487 per quality-adjusted life year. Conclusion: Doc-ADT is likely the optimal option from the perspective of both clinical outcomes and economic considerations.

Cost-effectiveness analysis of rasburicase over standard of care for the prevention and treatment of tumor lysis syndrome in children with hematologic malignancies in China.

Aims: To conduct a lifetime cost-effectiveness analysis (CEA) of rasburicase compared with standard of care (SOC) for tumor lysis syndrome (TLS) in children with hematologic malignancies from the Chinese healthcare system perspective. Materials and methods: The CEA was performed using a decision tree model with a lifetime horizon. The model explores the cost-effectiveness of rasburicase vs SOC for both preventing TLS and treating established TLS among pediatric patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), and non-Hodgkin's lymphoma (NHL). Both the prophylaxis-use model and treatment-use model incorporate long-term health states of the diseases: survival without TLS and death. The efficacy data of rasburicase and SOC were obtained from published literature. Drug costs, healthcare resource utilization (HRU), and adverse event (AE) management costs were obtained via a published study with clinical experts. Costs in US dollar and quality-adjusted life year (QALY) are reported, and incremental cost-effectiveness ratios (ICERs) were also calculated. Uncertainties due to parameter fluctuations in the model were assessed through one-way sensitivity analysis and probabilistic sensitivity analysis (PSA). Results: During TLS prevention, compared with SOC, the ICER of rasburicase treatment in China are $17,580.04/QALY, $5,783.45/QALY, and $5,391.00/QALY for pediatric patients with AML, ALL, and NHL, respectively. For the established TLS treatment, compared with SOC, the ICERs of rasburicase treatment are $2,031.18/QALY, $1,142.93/QALY, and $990.37/QALY for pediatric patients with AML, ALL, and NHL, respectively. Limitations: The clinical data for SOC are based on the published study in China, and the rasburicase prevention or treatment failure rate was either calculated based on the risk ratio or directly from the clinical study among non-Chinese pediatric patients. Another study limitation was the lack of utility data for pediatric patients with TLS and without TLS. Thus, the utility scores of pediatric cancer survivors were used as an alternative. Conclusion: Rasburicase is estimated to be a cost-effective alternative to SOC in the prevention and treatment of TLS among Chinese pediatric patients with AML, ALL, and NHL.

A Cost-effectiveness Analysis of Rabbit Antithymocyte Globulin Versus Antithymocyte Globulin-fresenius as Induction Therapy for Patients With Kidney Transplantation From Donation After Cardiac Death in China.

PURPOSE: Induction immunosuppression therapy is used to support optimal outcomes in kidney transplantation. This study was to assess the cost-effectiveness of rabbit antithymocyte globulin (r-ATG) versus ATG-Fresenius (ATG-F) in kidney transplantation in the Chinese setting from the perspective of the health care payer. METHODS: A 2-part survival model was developed, consisting of a short-term part and a long-term part. The short-term part analyzed the first year, using the decision tree, and consisted of the functioning transplant, acute rejection (AR), delayed graft function (DGF), dialysis, and death health states. The long-term part analyzed 2 to 5 years, using Markov model, and consisted of the functioning transplant, chronic dysfunction, recurring primary disease, dialysis, and death health states, with capture of the association between DGF and graft loss. Costs, including drug acquisition and other direct medical costs, were derived from China IQVIA database (formerly known as IMS) hospitaldatabase, chart review, and physician interviews. Clinical outcomes and utility were retrieved from published literature. The model calculated quality-adjusted life-years (QALYs) and total costs per patient. Costs and QALYs were discounted at an annual rate of 3.5%. Univariate sensitivity analysis and probability sensitivity analysis (PSA) were conducted to assess the impact of uncertainty of the variables on the results. FINDINGS: Patients who received r-ATG had more clinical effectiveness than patients who received ATG-F mainly because of less AR, DGF, and dialysis. The incremental QALY was 0.01 over a 1-year time horizon and 0.0496 over a 5-year time horizon. R-ATG and ATG-F drug costs were ¥10,783 and ¥8409, respectively. However, the total treatment costs of the r-ATG arm were lower than the ATG-F arm because of lower costs related to DGF, AR, dialysis, and adverse events. In total, r-ATG saved ¥5423 over the 1-year and ¥7042 over the 5-year time horizon. R-ATG was dominant with lower total direct medical costs and higher QALYs compared with ATG-F. Both univariate sensitivity analysis and PSA found the robustness of the model results. PSA results indicated that r-ATG was cost-effective compared with ATG-F in 86.81% of the simulations, considering <3 times the gross domestic product per capita as the threshold. IMPLICATIONS: From the perspective of the health care payer, r-ATG should be considered as the preferred treatment agent for induction therapy for Chinese patients undergoing kidney transplantation because of its lower overall medical costs and greater QALYs gained compared with ATG-F. The study was limited by lack of long-term efficacy data among the Chinese population and lack of comprehensive real-world higher quality costs data.

S100A4-MYH9 Axis Promote Migration and Invasion of Gastric Cancer Cells by Inducing TGF-ß-Mediated Epithelial-Mesenchymal Transition.

Driver genes conducing to peritoneal metastasis in advanced gastric cancer remain to be clarified. S100A4 is suggested to evolve in metastasis of gastrointestinal cancer, we aim to explore the role of S100A4 plays in metastasis of advanced gastric cancer and the potential mechanism. Transfection of siRNA or cDNA was applied to alter the expression of protein S100A4 and MYH9, investigation of the expression of epithelial and mesenchymal transition (EMT) associated markers was followed. Cell migration assay was used to screen the alteration of migration ability regulated by S100A4 and MYH9. IHC analysis for tissue sample microarray was performed to reveal their relationship with clinical pathological parameters and potential capacity of predicting survival. Consistent overexpression of S100A4 and MYH9 were found in peritoneal metastasis and primary site compared with adjacent normal tissue. Low expression of S100A4 led to increased epithelial markers as wells as decline of mesenchymal makers, while overexpression of S100A4 led to inverse impact. S100A4 expression was closely correlated with increased migration ability and EMT process induced by TGF-ß stimulation. Interference of S100A4 led to downregulation of MYH9 and inactivation of Smad pathway through participating in EMT process, which could be reversed by overexpression of MYH9. Moreover, co-expression of S100A4 and MYH9 was identified in tissue microarray and confirmed by immunofluorescence assay. In conclusion, overexpression of S100A4 and downstream molecular MYH9 in advanced gastric cancer predicted poor prognosis; oncogene S100A4 facilitate EMT process induced by TGF-ß stimulation, suggesting a potential target in management of peritoneal metastasis of gastric cancer.